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SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4), a key determinant of muscle action potential initiation. While dominant gain-of-function mutations in SCN4A are established causes of myotonia and periodic paralysis, autosomal recessive loss-of-function alleles have more recently been implicated in congenital myopathy ([PMID:26700687]).
Genetic analyses identified homozygous or compound heterozygous SCN4A variants in 11 individuals from six unrelated families presenting fetal or neonatal‐onset hypotonia, generalized weakness, and characteristic myopathic changes on muscle biopsy ([PMID:26700687]). Clinical features ranged from in utero akinesia with perinatal lethality to survivors with neonatal respiratory compromise and childhood spinal deformities followed by gradual improvement.
Additional case reports describe a Han Chinese patient with two missense SCN4A variants in trans (c.1841A>T (p.Asn614Ile) and c.4420G>A (p.Ala1474Thr)), presenting antenatal hypokinesia, polyhydramnios, neonatal hypotonia and respiratory distress, and progressive muscle weakness in later childhood ([PMID:38187266]).
The variant spectrum in congenital myopathy includes multiple predicted loss-of-function alleles such as c.501del (p.Tyr168fs) alongside nonsense, splice, and other frameshift mutations distributed throughout the channel gene. No founder variants have been reported to date.
Functional studies in HEK293 cells show that congenital myopathy–associated SCN4A mutations produce nonfunctional or severely attenuated Nav1.4 currents, consistent with a loss-of-function mechanism insufficient to sustain normal muscle excitability ([PMID:26700687]).
Taken together, the evidence supports a strong clinical validity for a recessive, loss-of-function mechanism of SCN4A in congenital myopathy. Routine inclusion of SCN4A in genetic panels for congenital myopathy can facilitate diagnosis and guide management.
Gene–Disease AssociationStrong11 probands from six unrelated families, multi-family segregation, concordant functional data Genetic EvidenceStrong11 biallelic loss-of-function variants in 11 probands across six families reached ClinGen genetic cap Functional EvidenceModerateIn vitro HEK293 studies demonstrate loss-of-function of Nav1.4 channels concordant with the myopathic phenotype |